Synthesis of a C-glycoside analogue of sTn: an HIV- and tumor-associated antigen.

N-Acetylneuraminic acid occupies the nonreducing end of many naturally occurring glycoconjugates on the cell surface, including glycoproteins and glycolipids. The strategic location of glycoconjugates on the cell surface and the enormous structural information that they carry account for their major role in biological recognition in the control of both normal and pathological processes.[1] While the participation of sialic acid in these biological events has been established unequivocally in a large number of studies,[1] the linkage of sialic acid to glycoconjugates is one of the most labile glycosidic linkages, which renders these compounds less amenable to biological and biochemical studies.[2] Terminal sialic acid residues are easily cleaved in vitro under very mild acidic conditions and in vivo by neuraminidases.[3] The biological importance of sialic acid coupled with its lability towards hydrolysis prompted us to redesign the molecular architecture of glycoconjugates to afford a nonhydrolyzable glycosidic linkage to sialic acid. Such a stable linkage should contribute to our understanding of biological recognition and serve to enhance or suppress biological events at the molecular level. The replacement of the interglycosidic oxygen atom with a hydroxymethylene or methylene group affords a new class of hydrolytically stable C-glycoside analogues of glycoconjugates.[4] A method for the preparation of C-glycosides of ulosonic acids using SmI2 was pioneered in our laboratory.[5] The sialyl-Tn epitope [a-d-Neu5Ac-(2!6)a-d-GalNAc(1!O)-Ser/Thr] (sTn, 1a, Figure 1) is found on the HIV envelope glycoprotein gp120[6] and in tumor-associated antigens present in the glycoproteins on the surface of cancer cells, including those associated with carcinomas of the breast, prostate, pancreas, colon, ovary, lung, and stomach.[7] Synthetic vaccines based on the sTn epitope (O-glycoside) have been recently prepared[8] and shown to stimulate an immune response.[9] Kishi and co-workers have demonstrated that C-glycosides and O-glycosides have similar conformational characteristics both in the free and bound states.[10] There are, nevertheless, differences in the population distribution of conformers adopted by C-glycosides and their natural counterparts.[11] However, the small energy differences among the various conformers allow them to interchange without any major energy conflicts, thus rendering the C-glycosides ideally suited as O-glycoside isosters for therapeutic evaluation. Our rationale for undertaking the synthesis of the C-glycoside